CN109846839B - Erythromycin ethylsuccinate granules and preparation method thereof - Google Patents
Erythromycin ethylsuccinate granules and preparation method thereof Download PDFInfo
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- CN109846839B CN109846839B CN201910095157.XA CN201910095157A CN109846839B CN 109846839 B CN109846839 B CN 109846839B CN 201910095157 A CN201910095157 A CN 201910095157A CN 109846839 B CN109846839 B CN 109846839B
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- erythromycin ethylsuccinate
- sodium bicarbonate
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- 229960000741 erythromycin ethylsuccinate Drugs 0.000 title claims abstract description 99
- NSYZCCDSJNWWJL-YXOIYICCSA-N erythromycin ethylsuccinate Chemical compound O1[C@H](C)C[C@H](N(C)C)[C@@H](OC(=O)CCC(=O)OCC)[C@@H]1O[C@H]1[C@@](O)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H]1C NSYZCCDSJNWWJL-YXOIYICCSA-N 0.000 title claims abstract description 99
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000008187 granular material Substances 0.000 title claims description 72
- 239000002245 particle Substances 0.000 claims abstract description 34
- 239000000080 wetting agent Substances 0.000 claims abstract description 33
- 235000021552 granulated sugar Nutrition 0.000 claims abstract description 25
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 20
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 20
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims abstract description 11
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 76
- 238000003756 stirring Methods 0.000 claims description 50
- 238000002156 mixing Methods 0.000 claims description 47
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 38
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 38
- 238000001035 drying Methods 0.000 claims description 35
- 239000007779 soft material Substances 0.000 claims description 31
- 239000000463 material Substances 0.000 claims description 23
- 238000004806 packaging method and process Methods 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 239000011812 mixed powder Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000203 mixture Substances 0.000 claims description 18
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 12
- 229930006000 Sucrose Natural products 0.000 claims description 12
- 239000002994 raw material Substances 0.000 claims description 12
- 238000007873 sieving Methods 0.000 claims description 11
- 238000007781 pre-processing Methods 0.000 claims description 10
- 238000010298 pulverizing process Methods 0.000 claims description 10
- 229920000136 polysorbate Polymers 0.000 claims description 4
- 238000004090 dissolution Methods 0.000 abstract description 17
- 239000003814 drug Substances 0.000 abstract description 10
- 230000000694 effects Effects 0.000 abstract description 4
- 239000000243 solution Substances 0.000 description 58
- 239000012535 impurity Substances 0.000 description 15
- 230000000052 comparative effect Effects 0.000 description 13
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 10
- 238000000034 method Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 239000007910 chewable tablet Substances 0.000 description 5
- 229940068682 chewable tablet Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 229960003276 erythromycin Drugs 0.000 description 5
- 238000012937 correction Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 229910019142 PO4 Inorganic materials 0.000 description 3
- 230000014759 maintenance of location Effects 0.000 description 3
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 3
- 239000010452 phosphate Substances 0.000 description 3
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 2
- AAEQXEDPVFIFDK-UHFFFAOYSA-N 3-(4-fluorobenzoyl)-2-(2-methylpropanoyl)-n,3-diphenyloxirane-2-carboxamide Chemical compound C=1C=CC=CC=1NC(=O)C1(C(=O)C(C)C)OC1(C=1C=CC=CC=1)C(=O)C1=CC=C(F)C=C1 AAEQXEDPVFIFDK-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 229930006677 Erythromycin A Natural products 0.000 description 2
- IDRYSCOQVVUBIJ-UHFFFAOYSA-N Erythromycin-B Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(C)C(CC)OC(=O)C(C)C1OC1CC(C)(OC)C(O)C(C)O1 IDRYSCOQVVUBIJ-UHFFFAOYSA-N 0.000 description 2
- MWFRKHPRXPSWNT-UHFFFAOYSA-N Erythromycin-C Natural products CC1C(OC2C(C(CC(C)O2)N(C)C)O)C(C)(O)CC(C)C(=O)C(C)C(O)C(O)(C)C(CC)OC(=O)C(C)C1OC1CC(C)(O)C(O)C(C)O1 MWFRKHPRXPSWNT-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000007764 Legionnaires' Disease Diseases 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- IDRYSCOQVVUBIJ-PPGFLMPOSA-N erythromycin B Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@H]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)C)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 IDRYSCOQVVUBIJ-PPGFLMPOSA-N 0.000 description 2
- 210000004211 gastric acid Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- HUKYDKSXFKBBIW-DTOMAXNRSA-N 4-[(2s,3r,4s,6r)-4-(dimethylamino)-2-[[(3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-2,10-dioxo-oxacyclotetradec-6-yl]oxy]-6-methyloxan-3-yl]oxy-4-ox Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)OC(=O)CCC(O)=O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 HUKYDKSXFKBBIW-DTOMAXNRSA-N 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- DKMROQRQHGEIOW-UHFFFAOYSA-N Diethyl succinate Chemical compound CCOC(=O)CCC(=O)OCC DKMROQRQHGEIOW-UHFFFAOYSA-N 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 208000001572 Mycoplasma Pneumonia Diseases 0.000 description 1
- 241000202934 Mycoplasma pneumoniae Species 0.000 description 1
- 201000008235 Mycoplasma pneumoniae pneumonia Diseases 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- 241000191940 Staphylococcus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
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- 210000005013 brain tissue Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
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- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical group CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
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- 229960003085 meticillin Drugs 0.000 description 1
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- 206010030861 ophthalmia neonatorum Diseases 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides an erythromycin ethylsuccinate particle and a preparation method thereof, wherein the erythromycin ethylsuccinate particle comprises the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 176-200 parts of white granulated sugar, 0.20-0.24 part of sodium bicarbonate, 0.8-0.8 part of tween-800.5, 15-18 parts of wetting agent and 0.7-0.9 part of essence. The dissolution rate of the prepared erythromycin ethylsuccinate particles meets the requirement by controlling the concentration of the wetting agent and the addition amount of the Tween 80, and meanwhile, the quality of the medicine is stable, so that the quality and the curative effect of the erythromycin ethylsuccinate particles are further ensured.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to erythromycin ethylsuccinate granules and a preparation method thereof.
Background
Erythromycin ethylsuccinate, which is the ethyl succinate of erythromycin, and has the Chinese alias: erythromycin ethylsuccinate, erythromycin succinate, erythromycin ethylsuccinate, and common pharmaceutical preparation such as granule, tablet, capsule, etc.
Erythromycin ethylsuccinate is a macrolide antibiotic, and is more stable in gastric acid than erythromycin. Has antibacterial activity against Staphylococcus (except methicillin-resistant strains), various groups of streptococcus and gram-positive bacillus, and is commonly used as substitute for penicillin-allergic patients. Has good effect on treating mycoplasma pneumonia, neonatal conjunctivitis, infant pneumonia, legionnaires 'disease and urogenital system infection caused by atypical pathogenic bacteria such as mycoplasma pneumoniae, chlamydia, legionnaires' disease and the like.
Erythromycin ethylsuccinate is easy to be absorbed by oral administration, and the medicine is stable in gastric acid and absorbed in intestinal tract in the form of matrix and esterified substance. The oral administration of 500mg of erythromycin ethylsuccinate on an empty stomach can lead the blood concentration to reach the peak value after 0.5 to 2 hours. After being absorbed, the medicine is widely distributed in various tissues and body fluids except cerebrospinal fluid and brain tissues, especially the concentration in liver, bile and spleen is high (can be more than dozens of times to dozens of times higher than blood concentration). Erythromycin ethylsuccinate is metabolized into inactive metabolite by liver.
Chinese patent publication No. CN 104434830A discloses an erythromycin ethylsuccinate chewable tablet and a preparation method thereof, wherein the chewable tablet comprises erythromycin ethylsuccinate, starch and sucrose, the method comprises the steps of firstly preparing a gelatinized corn starch solution, dissolving the sucrose in water to obtain a solution B, mixing the gelatinized corn starch solution and the solution B to obtain a gelatinized corn-sucrose system liquid medicine, adding main drug erythromycin ethylsuccinate into the gelatinized corn-sucrose system liquid medicine, fully and uniformly mixing, adding into a mold, freezing at low temperature, and adopting a two-reduction two-liter process to obtain the final chewable tablet. The tablet overcomes the defects of the common chewable tablet, reduces the types and the dosage of auxiliary materials in the erythromycin ethylsuccinate chewable tablet, has good performance and high bioavailability, but has poor dissolution rate.
In view of the above, there is a need in the art for erythromycin ethylsuccinate formulations with satisfactory dissolution rate and stable quality.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide erythromycin ethylsuccinate particles with dissolution rate meeting the requirement and stable quality and a preparation method thereof.
In order to achieve the purpose, the invention provides the following technical scheme:
an erythromycin ethylsuccinate granule comprises the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 176-200 parts of white granulated sugar, 0.20-0.24 part of sodium bicarbonate, 0.8-0.8 part of tween-800.5, 15-18 parts of wetting agent and 0.7-0.9 part of essence.
The wetting agent is 25-35% ethanol solution, preferably 30% ethanol solution.
The essence is orange flavor essence.
Further, the erythromycin ethylsuccinate granules comprise the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 184-192 parts of white granulated sugar, 0.21-0.23 part of sodium bicarbonate, 800.6-0.7 part of tween-9, 16-17 parts of wetting agent and 0.7-0.9 part of essence.
In one embodiment of the invention, the erythromycin ethylsuccinate particles comprise the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 188.8 parts of white granulated sugar, 0.224 part of sodium bicarbonate, 800.64 parts of tween-tween, 16.64 parts of wetting agent and 0.8 part of essence.
In another embodiment of the invention, the erythromycin ethylsuccinate granules comprise the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 192 parts of white granulated sugar, 0.23 part of sodium bicarbonate, 800.6 parts of tween-tween, 16 parts of wetting agent and 0.7 part of essence.
In another embodiment of the invention, the erythromycin ethylsuccinate granules comprise the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 184 parts of white granulated sugar, 0.21 part of sodium bicarbonate, 800.7 parts of tween-wetting agent, 17 parts of wetting agent and 0.9 part of essence.
The invention also provides a preparation method of the erythromycin ethylsuccinate granules, which comprises the steps of crushing and sieving the raw materials and auxiliary materials, mixing, preparing soft materials for granulation, drying granules, finishing granules, packaging and the like.
The preparation method of the erythromycin ethylsuccinate granules comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with water to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 12-18 minutes to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 12-18 minutes to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer for mixing;
and (c) packaging: and (6) inspecting, packaging and warehousing.
In the erythromycin ethylsuccinate granules:
in the step I, sodium bicarbonate is dissolved by water, and the weight ratio of the sodium bicarbonate to the water is 1: 1.3-1.5; the water is preferably 80-100 deg.C water.
In the second step, the stirring speed is 10-20 r/min, preferably 15 r/min.
In the third step, the stirring speed is 10-20 r/min, preferably 15 r/min.
In the step (iv), the drying temperature is 50-55 ℃, and the drying time is 80-100 minutes.
In the step (sixthly), the mixing time is 20-40 minutes, the stirring speed is 10-20 revolutions per minute, and the forward and reverse revolutions are respectively 10-20 minutes.
The dissolution rate refers to the dissolution rate and degree of the active drug from the granules under the specified conditions, the drug dissolution rate is an important index for the drug to exert the curative effect, the dissolution rate of the prepared erythromycin ethylsuccinate granules meets the requirement by controlling the concentration of the wetting agent and the adding amount of the Tween 80, and meanwhile, the quality of the drug is stable, thereby further ensuring the quality of the erythromycin ethylsuccinate granules and the exertion of the curative effect.
Detailed Description
The invention discloses erythromycin ethylsuccinate granules and a preparation method thereof, and the contents of the granules can be used for reference by the technical personnel in the field, and the formula proportion and the process parameters can be properly improved for realization. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention. While the invention has been described in terms of preferred embodiments, it will be apparent to those skilled in the art that variations may be applied, or changes and combinations may be made, in the methods and applications described herein to achieve and use the inventive techniques without departing from the spirit, scope, and content of the invention.
The present invention is further illustrated by the following examples, which are not intended to limit the invention in any way.
The test methods in the following examples are all conventional methods unless otherwise specified, and the raw materials, reagent materials and the like used in the following examples are all commercially available products unless otherwise specified.
According to the standard requirements of erythromycin ethylsuccinate granules in the second part of Chinese pharmacopoeia 2015 edition, the detection of each index is carried out.
The content of erythromycin ethylsuccinate in the product is 90.0-110.0% of the labeled amount.
Related substances are as follows:
taking a proper amount of the fine powder (about equal to 0.1g of erythromycin), placing the fine powder into a 25mL measuring flask, adding 10mL of methanol to dissolve the fine powder, diluting the fine powder to a scale by using a phosphate solution with the pH value of 8.0, shaking the fine powder uniformly, placing the fine powder for 16 hours at room temperature (20-25 ℃) to completely hydrolyze, filtering, and taking a subsequent filtrate as a sample solution; precisely measuring 1mL, placing in a 100mL measuring flask, diluting to scale with phosphate solution-methanol (3:2) with pH of 8.0, and shaking to obtain control solution; an appropriate amount of the control solution was precisely measured and quantitatively diluted with a phosphate solution of pH 8.0-methanol (3:2) to prepare a solution of about 4. mu.g/mL as a sensitive solution. And (3) detecting and simultaneously recording a chromatogram by adopting the following chromatographic conditions, and starting to calculate impurity peaks of the test solution after two succinic acid peaks after the solvent peak are eluted. The peak area of the impurity C is not more than 3 times (3.0%) of the main peak area of the solution, the peak areas (multiplied by a correction factor of 0.08) of the impurities E and F after correction are not more than 2 times (2.0%) of the main peak area of the control solution, the peak area (multiplied by a correction factor of 2) of the impurity D after correction is not more than 2 times (2.0%) of the main peak area of the control solution, and the peak areas of the impurity A, B and other single impurities are not more than 2 times (2.0%) of the main peak area of the control solution. The peak smaller than the main peak area of the sensitivity solution in the chromatogram of the test solution is ignored, and the sum of the corrected peak areas of the impurities is not more than 7 times (7.0%) of the main peak area of the control solution.
Chromatographic conditions are as follows: the retention time of an erythromycin A peak in the chromatogram is about 23 minutes, the relative retention times of the impurities A-F are about 0.4, 0.5, 0.9, 1.6, 2.3 and 1.8 respectively, and the relative retention times of erythromycin B and erythromycin C are about 1.7 and 0.55 respectively; the separation degree between the impurity B peak and the erythromycin C peak as well as between the erythromycin B peak and the impurity F peak is not less than 1.2, and the separation degree between the impurity C peak and the erythromycin A peak is in accordance with the requirement.
Dissolution rate: a paddle method is adopted, 0.1mol/L hydrochloric acid solution is used as a dissolution medium, the rotating speed is 50 r/min, the absorbance is measured at the wavelength of 482nm by an ultraviolet-visible spectrophotometry method, the dissolution percentage is calculated, and the dissolution percentage in 30 minutes is not lower than 80%.
Example 1: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.43 times of 90 deg.C water (100 ml) to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 50 ℃ for 110 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 30 minutes, wherein the stirring speed is 15 revolutions per minute, and the forward and reverse rotations are respectively 15 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Example 2: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.4 times of 90 deg.C water (101 ml) to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 55 ℃ for 80 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 40 minutes, wherein the stirring speed is 15 revolutions per minute, and the forward and reverse rotations are respectively carried out for 20 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Example 3: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.5 times of 80 deg.C water (86 ml) to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 52 ℃ for 90 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 20 minutes, wherein the stirring speed is 15 revolutions per minute, and the forward and reverse rotations are respectively carried out for 10 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Example 4: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.5 times of water (105 ml) at 80 deg.C to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 12 minutes at a stirring speed of 20 r/min to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 20 minutes at the stirring speed of 10 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 50 ℃ for 110 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 30 minutes, wherein the stirring speed is 15 revolutions per minute, and the forward and reverse rotations are respectively 15 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Example 5: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.3 times of 100 deg.C water (91 ml) to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 18 minutes at a stirring speed of 10 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 12 minutes at the stirring speed of 20 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 50 ℃ for 110 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 30 minutes, wherein the stirring speed is 14 revolutions per minute, and the forward and reverse rotations are respectively 15 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Example 6: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.5 times of 90 deg.C water (94.5 ml) to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 50 ℃ for 110 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 36 minutes, wherein the stirring speed is 16 revolutions per minute, and the forward and reverse revolutions are respectively 18 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Example 7: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; sodium bicarbonate was dissolved in 1.3 times of 90 ℃ water (97.5 ml) to obtain a sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 50 ℃ for 110 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 40 minutes, wherein the stirring speed is 12 revolutions per minute, and the forward and reverse revolutions are respectively 20 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Comparative example 1: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps: same as example 1
Comparative example 2: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with 1.43 times of 90 deg.C water (100 ml) to obtain sodium bicarbonate solution; adding a sodium bicarbonate solution into a wetting agent to obtain a solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 15 minutes at a stirring speed of 15 revolutions per minute to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles at 50 ℃ for 110 minutes;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a V-shaped mixer to mix for 30 minutes, wherein the stirring speed is 15 revolutions per minute, and the forward and reverse rotations are respectively 15 minutes;
and (c) packaging: and (6) inspecting, packaging and warehousing.
Comparative example 3: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
| components | weight/Kg | Number of parts |
| Erythromycin ethylsuccinate | 3.125 | 10 |
| White granulated sugar | 59 | 188.8 |
| Sodium bicarbonate | 0.07 | 0.224 |
| Tween-80 | 0.3 | 0.96 |
| 30% ethanol (Runzi)Wetting agent) | 5.2 | 16.64 |
| Essence | 0.25 | 0.8 |
The preparation method comprises the following steps: same as example 1
Comparative example 4: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
| components | weight/Kg | Number of parts |
| Erythromycin ethylsuccinate | 3.125 | 10 |
| White granulated sugar | 59 | 188.8 |
| Sodium bicarbonate | 0.07 | 0.224 |
| Tween-80 | 0.2 | 0.64 |
| 70% ethanol (wetting agent) | 5.2 | 16.64 |
| Essence | 0.25 | 0.8 |
The preparation method comprises the following steps: same as example 1
Comparative example 5: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
| components | weight/Kg | Number of parts |
| Erythromycin ethylsuccinate | 3.125 | 10 |
| White granulated sugar | 59 | 188.8 |
| Sodium bicarbonate | 0.07 | 0.224 |
| Tween-80 | 0.2 | 0.64 |
| 50% ethanol (wetting agent) | 5.2 | 16.64 |
| Essence | 0.25 | 0.8 |
The preparation method comprises the following steps: same as example 1
Comparative example 6: erythromycin ethylsuccinate granules
Prescription composition (2.5 ten thousand bags):
| components | weight/Kg | Number of parts |
| Erythromycin ethylsuccinate | 3.125 | 10 |
| White granulated sugar | 59 | 188.8 |
| Sodium bicarbonate | 0.07 | 0.224 |
| Tween-80 | 0.2 | 0.64 |
| 60% ethanol (wetting agent) | 5.2 | 16.64 |
| Essence | 0.25 | 0.8 |
The preparation method comprises the following steps: same as example 1
Example 8: stability test
Erythromycin ethylsuccinate granules prepared in examples 1-7 and comparative examples 1-6 were placed in a long-term stability test chamber (constant temperature and humidity chamber with temperature 25 ℃ + -2 ℃ and relative humidity 60% + -5%), sampled at 0, 3, 6, 9 and 12 months, and various indexes such as related substances, content, dissolution rate and the like were determined, and the results are shown in the following table:
as can be seen from the above table:
(1) the erythromycin ethylsuccinate granules prepared in the examples 1-7 have stable quality, and after being placed for 12 months under a long-term condition, all indexes such as related substances, content, dissolution rate and the like meet the requirements, and the quality is stable.
(2) Comparing and analyzing examples 1-7 and comparative examples 1-3, the adding amount of tween-80 affects the dissolution rate and quality stability of the erythromycin ethylsuccinate granules, when the adding amount of tween-80 is less (less than 0.5 part, comparative example 1) or tween-80 is not added (comparative example 2), the dissolution rate of the erythromycin ethylsuccinate granules prepared is lower, the dissolution percentage in 30 minutes is less than 80%, and the requirement is not met; when the adding amount of the Tween-80 is larger (higher than 0.8 part, comparative example 3), the dissolution rate of the prepared erythromycin ethylsuccinate particles meets the standard, but the stability of the erythromycin ethylsuccinate particles is influenced, the contents of the impurity B, other impurities and total impurities are sharply increased, and the standard is not met after the mixture is used for a long time of 12 months, so the adding amount of the Tween-80 is 0.5 to 0.8 part.
(3) Comparing and analyzing examples 1-7 and comparative examples 4-6, the concentration of the wetting agent ethanol solution influences the quality stability of the erythromycin ethylsuccinate granules, as shown in comparative examples 3-6, when the concentration of the ethanol solution is not less than 50%, the contents of the impurity A, the impurity C, the impurity D, other impurities and total impurities in the prepared erythromycin ethylsuccinate granules are increased sharply, and the contents do not meet the standard after 12 months, so the concentration of the wetting agent ethanol solution is 25% -35%.
Claims (10)
1. Erythromycin ethylsuccinate granules comprise the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 176-200 parts of white granulated sugar, 0.20-0.24 part of sodium bicarbonate, 0.8-0.8 part of tween-800.5, 15-18 parts of wetting agent and 0.7-0.9 part of essence, wherein the wetting agent is 25-35% ethanol solution;
the preparation method comprises the following steps:
preprocessing raw and auxiliary materials: pulverizing erythromycin ethylsuccinate and white sugar, and sieving with 80 mesh sieve; dissolving sodium bicarbonate with water to obtain sodium bicarbonate solution; adding sodium bicarbonate solution and tween-80 into wetting agent to obtain solution A;
② mixing raw materials and auxiliary materials uniformly: adding erythromycin ethylsuccinate and white granulated sugar into a mixer, and stirring and mixing for 12-18 minutes to obtain mixed powder B;
thirdly, preparing soft material and granulating: adding the solution A prepared in the step I into the mixed powder B, stirring and mixing for 12-18 minutes to prepare a soft material; granulating the prepared soft material by a 20-mesh screen;
and fourthly, drying: drying the prepared particles;
granule finishing: after drying, adding essence, and finishing granules by using a 16-mesh screen to prepare granules with uniform size;
sixthly, total mixing: adding the prepared particles into a mixer for mixing;
and (c) packaging: and (6) inspecting, packaging and warehousing.
2. The erythromycin ethylsuccinate granule as claimed in claim 1, wherein the prescription composition comprises, in parts by weight: 10 parts of erythromycin ethylsuccinate, 184-192 parts of white granulated sugar, 0.21-0.23 part of sodium bicarbonate, 800.6-0.7 part of tween-9, 16-17 parts of wetting agent and 0.7-0.9 part of essence.
3. The erythromycin ethylsuccinate particle as claimed in claim 1, which comprises the following components in parts by weight: 10 parts of erythromycin ethylsuccinate, 188.8 parts of white granulated sugar, 0.224 part of sodium bicarbonate, 800.64 parts of tween-tween, 16.64 parts of wetting agent and 0.8 part of essence.
4. The erythromycin ethylsuccinate granule as claimed in claim 1, wherein the prescription composition comprises, in parts by weight: 10 parts of erythromycin ethylsuccinate, 192 parts of white granulated sugar, 0.23 part of sodium bicarbonate, 800.6 parts of tween-tween, 16 parts of wetting agent and 0.7 part of essence.
5. The erythromycin ethylsuccinate granule according to claim 1, wherein the prescription composition is: 10 parts of erythromycin ethylsuccinate, 184 parts of white granulated sugar, 0.21 part of sodium bicarbonate, 800.7 parts of tween-wetting agent, 17 parts of wetting agent and 0.9 part of essence.
6. The erythromycin ethylsuccinate particle as claimed in claim 1, wherein in the step (i), the sodium bicarbonate is dissolved in water, and the weight ratio of the sodium bicarbonate to the water is 1: 1.3-1.5; the water is water with the temperature of 80-100 ℃.
7. The erythromycin ethylsuccinate particle as claimed in claim 1, wherein in the step (II), the stirring speed is 10-20 rpm.
8. The erythromycin ethylsuccinate particle as claimed in claim 1, wherein in the step (iv), the drying temperature is 50-55 ℃ and the drying time is 80-100 minutes.
9. The erythromycin ethylsuccinate particle as claimed in claim 1, wherein in the step (sixthly), the mixing time is 20-40 minutes, the stirring speed is 10-20 revolutions per minute, and the forward and reverse rotations are respectively 10-20 minutes.
10. The erythromycin ethylsuccinate particle as claimed in claim 1, wherein in the step (II), the stirring speed is 15 rpm.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4076804A (en) * | 1975-07-18 | 1978-02-28 | Abbott Laboratories | Erythromycin therapy |
| CN1110912A (en) * | 1994-04-30 | 1995-11-01 | 杭州市药物研究所 | Method for improving performance of tablet and granular medicines |
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2019
- 2019-01-31 CN CN201910095157.XA patent/CN109846839B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4076804A (en) * | 1975-07-18 | 1978-02-28 | Abbott Laboratories | Erythromycin therapy |
| CN1110912A (en) * | 1994-04-30 | 1995-11-01 | 杭州市药物研究所 | Method for improving performance of tablet and granular medicines |
Non-Patent Citations (1)
| Title |
|---|
| 琥乙红霉素颗粒生产工艺的改进;张朋臻，等;《齐鲁药事》;20051231;第24卷(第7期);440 * |
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